What is the management of acute adrenal insufficiency, including diagnosis, laboratory tests, and treatment with medications such as hydrocortisone (corticosteroid)?

Acute Adrenal Insufficiency (Adrenal Crisis): Clinical Illness Script

Usual Patient Profile

Patients with acute adrenal crisis typically fall into two categories: those with known adrenal insufficiency who experience a precipitating event, or those presenting de novo with undiagnosed disease. 1, 2

Demographics and Risk Factors

• Primary adrenal insufficiency (Addison's disease): Most commonly caused by autoimmune adrenalitis (~85% in Western populations), affecting adults of any age 3
• Secondary adrenal insufficiency: Most frequently from hypothalamic-pituitary tumors or chronic glucocorticoid therapy withdrawal 4
• Incidence of crisis: 6-8 episodes per 100 patient-years in known PAI patients 1
• Mortality risk: 0.5 deaths per 100 patient-years if untreated 5

Key Clinical Clues from History of Present Illness

Cardinal Presenting Symptoms

• Hypotension and shock (often severe and refractory to vasopressors) 2, 3
• Severe dehydration with volume depletion 1, 2, 3
• Gastrointestinal symptoms: Nausea, vomiting (often severe), abdominal pain (sometimes mimicking acute abdomen with peritoneal irritation) 1, 2, 3
• Profound malaise and fatigue 1, 2, 3
• Muscle pain or cramps 1, 2, 3
• Neurological manifestations: Confusion, impaired cognitive function, loss of consciousness, or coma in severe cases 1, 2, 3

Critical Pitfall

Even mild gastrointestinal upset can precipitate crisis because patients cannot absorb their oral medications when they need them most. 1, 3

Past Medical History Red Flags

Most Common Precipitating Events

• Gastrointestinal illness with vomiting/diarrhea (most common trigger) 1, 2, 3
• Any infection (bacterial or viral) 1, 2
• Surgical procedures without adequate steroid coverage 1, 2, 3
• Physical trauma or injuries 1, 2, 3
• Myocardial infarction 1, 2, 3
• Severe allergic reactions 1, 2, 3
• Severe hypoglycemia in diabetic patients 1, 2, 3

Iatrogenic and Management-Related Causes

• Failure to increase glucocorticoid doses during intercurrent illness despite patient education 3
• Chronic under-replacement with fludrocortisone combined with low salt intake 3
• Medications accelerating cortisol clearance (e.g., rifampin, phenytoin, barbiturates) without dose adjustment 3
• Starting thyroid hormone replacement before adequate glucocorticoid replacement in patients with multiple hormone deficiencies 3
• Rapid tapering of high-dose corticosteroids in patients treated with immune checkpoint inhibitors 3
• Poor compliance with mineralocorticoid therapy 3

Relevant Past Medical History

• Known adrenal insufficiency (primary or secondary) 1, 6
• Autoimmune conditions (thyroid disease, type 1 diabetes, vitiligo) suggesting autoimmune polyendocrine syndrome 3
• History of tuberculosis or fungal infections (infiltrative causes) 3
• Pituitary disease or cranial radiation (secondary causes) 4
• Recent discontinuation of chronic glucocorticoid therapy 5

Family History

• Autoimmune diseases (thyroid disease, type 1 diabetes, pernicious anemia) 3
• Congenital adrenal hyperplasia (most frequent cause in children) 5
• Adrenoleukodystrophy (X-linked genetic disorder) 3

Personal and Social History

• Medication compliance patterns (critical for known adrenal insufficiency patients) 1, 3
• Underlying psychiatric disorders (associated with recurrent crises and poor compliance) 3
• Salt intake habits (chronic low salt consumption increases crisis risk) 3
• Physical activity patterns (unaccustomed intense exercise can precipitate crisis) 1
• Travel history (exposure to infections, gastrointestinal illness) 1
• Medical alert identification (presence or absence) 7, 2

Physical Examination Findings

Vital Signs

• Severe hypotension (often <90/60 mmHg) 2, 3
• Tachycardia 2
• Fever (if infection is precipitating cause) 1

Key Physical Findings

• Hyperpigmentation of skin and mucous membranes (classic sign of primary adrenal insufficiency due to elevated ACTH) 3
• Signs of severe dehydration: Poor skin turgor, dry mucous membranes, sunken eyes 1, 3
• Altered mental status: Confusion, lethargy, or coma 1, 2, 3
• Abdominal tenderness (may mimic acute abdomen) 1, 3

Laboratory Tests to Order Immediately

Critical Pre-Treatment Labs (Draw Before Treatment, But Never Delay Therapy)

Blood samples must be obtained before initiating treatment, but treatment must NEVER be delayed waiting for results. 1, 7, 2, 3

• Serum cortisol (random level <10 mcg/dL or <250 nmol/L suggests adrenal insufficiency) 3
• Plasma ACTH (markedly elevated in primary adrenal insufficiency) 1, 7, 3
• Serum sodium (hyponatremia present in ~90% of cases) 3
• Serum potassium (hyperkalemia in ~50% of cases) 3
• Serum creatinine and BUN (elevated due to prerenal renal failure) 1, 7, 3
• Serum glucose (hypoglycemia common in children, less frequent in adults) 1, 7, 3
• Serum calcium (mild hypercalcemia in 10-20% of cases) 3

Additional Diagnostic Tests

• Blood cultures and tests for precipitating infections (bacterial or viral) 1, 7
• Arterial blood gas (metabolic acidosis common) 3

Diagnostic Pitfalls

• Absence of hyperkalemia does NOT exclude adrenal crisis (present in only 50% of cases) 3
• Absence of hyponatremia should not prevent treatment if clinical suspicion is high 3
• ACTH stimulation test should NOT be used to decide who receives treatment in acute crisis 2, 8

Imaging Studies

Acute Phase

• Chest X-ray (to evaluate for infection as precipitating cause) 1
• CT abdomen (if diagnosis unclear or to evaluate adrenal hemorrhage, tumor, or infiltrative disease) 3

After Stabilization (Etiologic Workup)

• CT scan of adrenals (if 21-hydroxylase autoantibodies negative, to evaluate for hemorrhage, tumor, tuberculosis, or infiltrative processes) 3
• MRI pituitary (if secondary adrenal insufficiency suspected) 4

Emergency Management: The Critical First Hour

Immediate Actions (Do Not Delay for Diagnostic Confirmation)

Administer hydrocortisone 100 mg IV bolus immediately upon clinical suspicion of adrenal crisis—this is the single most important intervention and must not be delayed. 1, 7, 2, 3, 9

Step 1: Glucocorticoid Administration

• Hydrocortisone 100 mg IV bolus (this high dose saturates 11β-hydroxysteroid dehydrogenase type 2, providing necessary mineralocorticoid effect) 1, 7, 2, 3
• Do NOT use dexamethasone (not recommended for critical illness-related corticosteroid insufficiency) 8

Step 2: Aggressive Fluid Resuscitation

• 0.9% isotonic saline 1 liter IV over the first hour 1, 7, 2, 3
• Continue with 3-4 liters total over 24-48 hours with frequent hemodynamic monitoring 1, 7, 2, 3
• In children: Initial bolus of 10-20 mL/kg (maximum 1,000 mL) 3

Step 3: Draw Pre-Treatment Labs

• Obtain blood samples for cortisol, ACTH, electrolytes, creatinine, urea, glucose, and infection workup 1, 7, 2
• Critical: Do NOT wait for results before starting treatment 1, 7, 2, 3

Ongoing Management (First 24-48 Hours)

Continued Glucocorticoid Therapy

Continue hydrocortisone 100-300 mg/day, either as continuous IV infusion (10 mg/hr = 240 mg/day) or as divided IV/IM boluses of 100 mg every 6 hours. 1, 7, 2, 3

Fluid Management

• Continue slower isotonic saline infusion with frequent hemodynamic monitoring to avoid fluid overload 1, 7, 2
• Monitor serum electrolytes frequently to guide fluid management 1, 7, 2

Supportive Care

• ICU or high-dependency unit admission for severe cases with persistent hypotension 7, 2, 3
• Gastric stress ulcer prophylaxis 7, 2
• Low-dose heparin prophylaxis (depending on severity) 7, 2
• Antibiotic treatment if infection is precipitating cause 1, 7, 2

Critical Management Pitfall

Do NOT add separate mineralocorticoid (fludrocortisone) during acute crisis management—the high-dose hydrocortisone provides adequate mineralocorticoid activity. 3

Transition to Oral Therapy (After 1-3 Days)

Taper parenteral glucocorticoids over 1-3 days to oral maintenance therapy once the patient is stabilized and can tolerate oral medications. 7, 2, 3

Maintenance Glucocorticoid Replacement

• Hydrocortisone 15-25 mg daily in 2-3 divided doses (e.g., 10 mg upon awakening, 5 mg at noon, 5 mg at 4-6 PM) 1, 7, 6
• Preference for short-acting hydrocortisone over longer-acting agents like prednisone 3

Mineralocorticoid Replacement (Primary Adrenal Insufficiency Only)

• Fludrocortisone 50-200 mcg daily as single morning dose 1, 7, 6

Weaning Strategy

• Glucocorticoids should be weaned gradually, not stopped abruptly 2, 8
• Reinstitute high-dose treatment if signs of sepsis, hypotension, or worsening oxygenation recur 8

Special Situations: Stress Dosing Protocols

Major Surgery with Long Recovery

• 100 mg hydrocortisone IM just before anesthesia 1, 7
• Continue 100 mg hydrocortisone IM every 6 hours until able to eat and drink 1, 7
• Then double oral dose for 48+ hours, then taper to normal dose 1

Major Surgery with Rapid Recovery

• 100 mg hydrocortisone IM just before anesthesia 1
• Continue 100 mg hydrocortisone IM every 6 hours for 24-48 hours 1
• Then double oral dose for 24-48 hours, then taper to normal dose 1

Minor Surgery and Major Dental Surgery

• 100 mg hydrocortisone IM just before anesthesia 1
• Double oral dose for 24 hours, then return to normal dose 1

Minor Illness with Fever

• Double or triple oral glucocorticoid dose for 24-48 hours 7, 2
• If unable to tolerate oral medications, use parenteral hydrocortisone 3

Labor and Vaginal Birth

• 100 mg hydrocortisone IM at onset of labor 1
• Repeat if necessary every 6 hours 1
• Double oral dose for 24-48 hours postpartum 1

Invasive Bowel Procedures Requiring Laxatives

• Hospital admission overnight with 100 mg hydrocortisone IM and IV fluids 1
• Repeat dose before start of procedure 1
• Double oral dose for 24 hours after procedure 1

Prevention of Future Crises: Patient Education Essentials

Emergency Supplies and Identification

• Provide emergency supplies of injectable hydrocortisone (100 mg IM kit) 7, 2
• Medical alert jewelry and emergency steroid card (triggers stress-dose corticosteroids by emergency personnel) 7, 2, 3

Sick Day Rules Education

• Double or triple oral dose during minor illness with fever 7, 2
• Use parenteral hydrocortisone if vomiting or unable to take oral medications 3
• Increase salt and fluid intake during hot weather or intense physical activity 1
• Never skip doses, even with mild gastrointestinal upset 1, 3

Follow-Up Care

• Schedule regular follow-up at least annually to assess health, weight, blood pressure, and electrolytes 7
• Early endocrinology consultation for ongoing management and education 3
• After any crisis, evaluate precipitating cause and review patient's understanding of stress dosing 2

Etiologic Workup (After Stabilization)

Primary vs. Secondary Adrenal Insufficiency

• Test for 21-hydroxylase autoantibodies (21OH-Ab) (positive in ~85% of autoimmune Addison's disease) 3
• If 21OH-Ab negative, obtain CT scan of adrenals to evaluate for hemorrhage, tumor, tuberculosis, or infiltrative processes 3
• Test very long chain fatty acids (VLCFA) if adrenoleukodystrophy suspected 3
• MRI pituitary if secondary adrenal insufficiency suspected 4

ACTH Stimulation Test (For Diagnosis, Not Acute Management)

• Delta total serum cortisol <9 mcg/dL after ACTH (250 mcg) administration suggests adrenal insufficiency 8
• Random total cortisol <10 mcg/dL with elevated ACTH is diagnostic of primary adrenal insufficiency 3
• This test should NOT be used to decide who receives treatment in acute crisis 2, 8

Key Clinical Pearls

• Mortality increases with delayed intervention—when in doubt, treat immediately 3
• Consider adrenal crisis in any patient with unexplained collapse, hypotension, vomiting, or diarrhea, especially with electrolyte abnormalities 3
• The frequency of adrenal crisis is 6-8 per 100 patient-years, making prevention through education critical 1, 5
• Never start thyroid hormone replacement before adequate glucocorticoid replacement in patients with multiple hormone deficiencies 3
• Underlying psychiatric disorders and poor compliance should be investigated in patients with recurrent crises 3